The present invention relates to novel 2-methylpropionic acid derivatives and pharmaceutically acceptable salts thereof which are useful as medicaments.
It is known that three subtypes of sympathetic xcex2-adrenoceptors, which have been classified as xcex21, xcex22 and xcex23, are present and that each receptor subtype is distributed in specified organs in living body and has a specific function.
For example, xcex21-adrenoceptor is mainly present in the heart and the stimulation of this receptor leads to an increase of heart rate and cardiac contractility. xcex22-Adrenoceptor is mainly present in the smooth muscle of blood vessels, the trachea and uterus. The stimulation of this receptor leads to vasodilatation, bronchodilation and inhibition of uterine contraction. xcex23-Adrenoceptor is mainly present in adipocytes, the gallbladder and intestinal tract. It is known that xcex23-adrenoceptor is also present in the brain, liver, stomach and prostate. It is reported that the stimulation of this receptor leads to an increase of lipolysis, inhibition of intestinal tract motility, an increase of glucose uptake, anti-depression and so on (Drugs of the Future, Vol.18, No.6, pp.529-549 (1993); Molecular Brain Research, Vol.29, pp.288-297 (1995);
In addition, it is recently reported that in the human bladder xcex23-adrenoceptor is predominantly present and that the human bladder is relaxed by xcex23-adrenoceptor stimulants (The Japanese Journal of Urology, Vol.88, No.2, p.183 (1997); NEUROUROLOGY AND URODYNAMICS, Vol.16, No.5, pp.363-365 (1997)).
Many xcex21-adrenoceptor stimulants and xcex22-adrenoceptor stimulants have been developed and are used for medicinal purposes as cardiotonics, bronchodilators, preventive agents for threatened abortion or premature labor, and so on.
On the other hand, it has been found that xcex23-adrenoceptor stimulants are useful as agents for the prevention or treatment of obesity, hyperglycemia, the diseases caused by intestinal hypermotility, pollakiuria, urinary incontinence, depression, the diseases caused by biliary calculi or hypermotility of biliary tract and so on. Consequently, studies have been made to develop excellent xcex23-adrenoceptor stimulants, but no xcex23-adrenoceptor stimulant has been sold yet (Drugs of the Future, Vol.18, No.6, pp.529-549(1993); European Journal of Pharmacology, Vol.219, pp.193-201(1992) etc.).
Therefore, it has been greatly desired to develop novel xcex23-adrenoceptor stimulants having excellent xcex23-adrenoceptor stimulating effects.
More preferably, it has been desired to develop highly selective and novel xcex23-adrenoceptor stimulants having potent xcex23-adrenoceptor stimulating effects in comparison with xcex21 and/or xcex22-adrenoceptor stimulating effects and resulting in reduced side effects such as palpitation and tremor caused by xcex21 and xcex22-adrenoceptor stimulating effects.
The present invention relates to a 2-methylpropionic acid derivative represented by the general formula: 
(wherein R1 represents a hydrogen atom, a lower alkyl group or an aralkyl group; R2 represents a hydrogen atom, a lower alkyl group or a halogen atom; A represents an oxygen atom or an imino group; the carbon atom marked with (R) represents a carbon atom in R configuration; and the carbon atom marked with (S) represents a carbon atom in S configuration) or a pharmaceutically acceptable salt thereof.
The present invention relates to a pharmaceutical composition comprising as the active ingredient a 2-methyl-propionic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
The present invention relates to an agent for the prevention or treatment of obesity, hyperglycemia, the diseases caused by intestinal hypermotility, pollakiuria, urinary incontinence, depression, or the diseases caused by biliary calculi or hypermotility of biliary tract which comprises as the active ingredient a 2-methylpropionic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
The present invention relates to a method for the prevention or treatment of obesity, hyperglycemia, the diseases caused by intestinal hypermotility, pollakiuria, urinary incontinence, depression, or the diseases caused by biliary calculi or hypermotility of biliary tract which comprises administering a therapeutically effective amount of a 2-methylpropionic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
The present invention relates to a use of a 2-methyl-propionic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of obesity, hyperglycemia, the diseases caused by intestinal hypermotility, pollakiuria, urinary incontinence, depression, or the diseases caused by biliary calculi or hypermotility of biliary tract.
The present invention relates to a use of a 2-methyl-propionic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as an agent for the prevention or treatment of obesity, hyperglycemia, the diseases caused by intestinal hypermotility, pollakiuria, urinary incontinence, depression, or the diseases caused by biliary calculi or hypermotility of biliary tract.
The present invention relates to a process for the manufacture of a pharmaceutical composition for the prevention or treatment of obesity, hyperglycemia, the diseases caused by intestinal hypermotility, pollakiuria, urinary incontinence, depression, or the diseases caused by biliary calculi or hypermotility of biliary tract, characterized in the use, as an essential constituent, of a 2-methylpropionic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
The present inventors have studied extensively to meet the above objects. As a result, it was found that 2-methyl-propionic acid derivatives represented by the above general formula (I) and pharmaceutically acceptable salts thereof have excellent 62 3-adrenoceptor stimulating effects, thereby forming the basis of the present invention.
In the present invention, the term xe2x80x9clower alkyl groupxe2x80x9d means a straight or branched alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, an isobutyl group, a pentyl group, an isopentyl group, a hexyl group and the like; the term xe2x80x9caralkyl groupxe2x80x9d means the above lower alkyl group substituted by an aryl group such as a phenyl group, a naphthyl group and the like; and the term xe2x80x9chalogen atomxe2x80x9d means a fluorine atom, a chlorine atom, a bromine atom and the like.
The compounds represented by the above general formula (I) of the present invention can be prepared according to the following procedure. For example, the compounds of the present invention can be prepared by allowing an amine compound represented by the formula: 
(wherein the carbon atom marked with (R) and the carbon atom marked with (S) have the same meanings as defined above) to react with an alkylating agent represented by the general formula: 
(wherein R1a represents a lower alkyl group or an aralkyl group; X represents a leaving group; and R2and A have the same meanings as defined above) in the presence or absence of a base such as N,N-diisopropylethylamine in an inert solvent such as N,N-dimethylformamide, and converting the ester group into a carboxyl group in the usual way as occasion demands.
The amine compound represented by the above formula (II) which is used as a starting material in the above production process can be prepared by optical resolution of a commercially available enantiomeric mixture in the usual way or a method described in a literature (e.g., J. Med. Chem., Vol. 20, No. 7, pp.978-981(1977)).
The compounds represented by the above general formula (III) which are used as starting materials in the above production process can be prepared according to the following procedures. For example, the compounds can be prepared by allowing a compound represented by the general formula: 
(wherein R3 represents a hydroxy group having a protective group; A1 represents a hydroxy group or an amino group; and R2 has the same meaning as defined above) to react with 1,1,1-trichloro-2-methyl-2-propanol or chloroform in the presence of a base such as potassium hydroxide or sodium hydroxide in acetone, subjecting the resulting compound to esterification in the usual way to give a compound represented by the general formula: 
(wherein R1a, R2, R3 and A have the same meanings as defined above), removing the hydroxy-protective group and converting the hydroxy group into a leaving group in the usual way.
Of the compounds represented by the above general formula (III) which are used in the above production process, the compounds represented by the general formula: 
(wherein X1 represents a chlorine atom or a bromine atom; and R1a and R2have the same meanings as defined above) can be prepared by subjecting a compound represented by the general formula: 
(wherein R1a and R2 have the same meanings as defined above) to Friedel-Crafts reaction using an acid halide represented by the general formula: 
(wherein X2 represents a hydrogen atom, a chlorine atom or a bromine atom; and X3 represents a chlorine atom or a bromine atom), subjecting the resulting compound to bromination or chlorination of the acetyl group in the usual way as occasion demands, and reducing the carbonyl group at the benzyl position using a reducing agent such as triethylsilane.
The compounds represented by the above general formula (VI) which are used as starting materials in the above production process can be prepared, for example, 1) by allowing a compound represented by the general formula: 
(wherein R2has the same meaning as defined above) to react with 1,1,1-trichloro-2-methyl-2-propanol or chloroform in the presence of a base such as potassium hydroxide or sodium hydroxide in acetone and subjecting the resulting compound to esterification in the usual way, or 2) by allowing a compound represented by the above general formula (VIII) to react with an alkyl 2-bromoisobutyrate in the presence of a base such as cesium carbonate in N,N-dimethylformamide.
The compounds represented by the above general formula (IV) which are used as starting materials in the above production process can be prepared by using the corresponding phenol derivative or aniline derivative according to methods described in the literature or methods analogous thereto (Org. Synth., collect. Vol.111, pp.183-184(1955); J. Med. Chem., Vol.15, No.5, pp.490-493(1972); J. Med. Chem., Vol.28, No.12, pp.1828-1832(1985) etc.).
For example, the compounds represented by the above general formula (IV) can be prepared by subjecting a compound represented by the general formula: 
(wherein A2 represents a protected hydroxy group or a protected amino group; and R2 has the same meaning as defined above) to Friedel-Crafts reaction using bromoacetyl bromide to give a compound represented by the general formula: 
(wherein R2 and A2 have the same meanings as defined above), reducing the compound with a reducing agent such as sodium borohydride, treating the resulting compound with a base such as potassium carbonate to give an epoxy compound represented by the general formula: 
(wherein R2 and A2 have the same meanings as defined above), opening the epoxy group in the usual way, subjecting the resulting compound to protection of the resulting alcoholic hydroxy group and removing the protective group of the phenolic hydroxy group or the amino group in the usual way.
The compounds represented by the above general formula (IV) can be prepared by subjecting the phenolic hydroxy group or the amino group of a compound represented by the general formula: 
(wherein R2 and A1 have the same meanings as defined above) to protection temporarily using chloromethyl methyl ether, trifluoroacetic anhydride or the like, converting the alcoholic hydroxy group of the resulting compound into a hydroxy-protective group which is stable under an alkaline condition such as a benzyl ether, a benzyloxymethyl ether or the like, and removing the protective group of the phenolic hydroxy group or the amino group in the usual way.
Of the compounds represented by the above general formula (IV), the compounds represented by the general formula: 
(wherein R2 and R3 have the same meanings as defined above) can be prepared by converting the alcoholic hydroxy group of a compound represented by the general formula: 
(wherein R2 has the same meaning as defined above) into a protective group which is stable under an alkaline condition such as a benzyl ether, a benzyloxymethyl ether, methoxymethyl ether or the like, and reducing the nitro group in the usual way.
In the above production process, the term xe2x80x9cleaving groupxe2x80x9d means a leaving group generally used for N-alkylation such as a p-toluenesulfonyloxy group, a methanesulfonyloxy group, a chlorine atom, a bromine atom, an iodine atom and the like.
The 2-methylpropionic acid derivatives represented by the above general formula (I) of the present invention can be converted into their pharmaceutically acceptable salts in the usual way. Examples of such salts include acid addition salts formed with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like; acid addition salts formed with organic acids such as formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid and the like; inorganic base salts such as a sodium salt, a potassium salt, a calcium salt and the like; and salts formed with organic bases such as triethylamine, piperidine, morpholine, pyridine, lysine and the like.
The compounds of the present invention obtained by the above production process can be isolated and purified by conventional separation means such as fractional recrystallization, purification using chromatography and solvent extraction.
The compounds of the present invention include their solvates with pharmaceutically acceptable solvents such as water and ethanol.
xcex23-Adrenoceptor stimulating effects of the compounds represented by the above general formula (I) of the present invention were studied according to the following procedure.
Namely, urinary bladders of ferrets were isolated and preparations were made. The experiment was conducted according to the Magnus method. The ureteral tension without the addition of the drug is expressed as 100%, and the tension of maximal relaxation after the addition of 10xe2x88x925M of forscolin was expressed as 0%. The drug was added cumulatively. The xcex23-adrenoceptor stimulating effects were evaluated as the concentration of the drug required to produce 50% decrease of the tension (i.e., EC50 value) (The Japanese Journal of Urology, Vol.89, No.2, p.272 (1998)).
For example, xcex23-adrenoceptor stimulating effect (EC50 value) of 2-[3-chloro-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]-2-methylpropionic acid was 1.9xc3x9710xe2x88x928M.
Thus, the compounds represented by the above general formula (I) of the present invention are excellent xcex23-adrenoceptor stimulants having excellent xcex23-adrenoceptor stimulating effects.
As preferable compounds in the present invention, 2-methyipropionic acid derivatives represented by the general formula: 
(wherein R2, A, the carbon atom marked with (R) and the carbon atom marked with (S) have the same meanings as defined above) and pharmaceutically acceptable salts thereof having potent xcex23-adrenoceptor stimulating effects compared with xcex21 and xcex22-adrenoceptor stimulating effects can be illustrated.
The xcex21-adrenoceptor stimulating effects and xcex22-adrenoceptor stimulating effects of the compounds represented by the above general formula (I) of the present invention were studied according to the following procedures.
Namely, atria of rats were isolated and preparations were made. The experiment was conducted according to the Magnus method. The increment of heart rate after the addition of isoproterenol (10xe2x88x928M) was expressed as 100%. The drug was added cumulatively. The xcex21-adrenoceptor stimulating effects were evaluated as the concentration of the drug required to produce 50% increase of heart rate (i.e., EC50 value).
Also, uteri of pregnant rats were isolated and preparations were made. The experiment was conducted according to the Magnus method. The sum of uterine contractions during 5 minutes before the addition of the drug was expressed as 100%. The drug was added cumulatively. The xcex22-adrenoceptor stimulating effects were evaluated as the concentration of the drug required when the sum of the contractions during 5 minutes after the addition of the drug produces 50% decrease of the sum of the contractions during 5 minutes before the addition of the drug (i.e., EC50 value).
For example, xcex21 and xcex22-adrenoceptor stimulating effects of 2-[3-chloro-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxy-phenyl)-1-methylethyl]amino]ethyl]phenoxy]-2-methyl-propionic acid were 3.5xc3x9710xe2x88x925M (EC50 value) and 3.1xc3x9710xe2x88x926M (EC50 value), respectively. This compound is an extremely suitable compound as an excellent xcex23-adrenoceptor stimulant with highly reduced xcex21 and xcex22-adrenoceptor stimulating effects.
The 2-methyipropionic acid derivatives represented by the above general formula (I) and pharmaceutically acceptable salts thereof of the present invention have excellent xcex23-adrenoceptor stimulating effects and are very useful compounds as medicaments such as an agent for the prevention or treatment of obesity, hyperglycemia, the diseases caused by intestinal hypermotility, pollakiuria, urinary incontinence, depression, the diseases caused by biliary calculi or hypermotility of biliary tract, or the like.
Furthermore, the compounds represented by the above general formula (I) of the present invention are very safe compounds. For example, in acute toxicity testing using rats, when 2-[3-chloro-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]-2-methylpropionic acid was administered at a dose of 400 mg/kg, no death was observed.
When the 2-methylpropionic acid derivatives represented by the above general formula (I) and pharmaceutically acceptable salts thereof of the present invention are employed in the practical treatment, they are administered orally or parenterally in the form of compositions such as powders, granules, fine granules, tablets, capsules, injections, solutions, ointments, suppositories and the like. These pharmaceutical compositions can be formulated in accordance with conventional methods using conventional pharmaceutical carriers, excipients and other additives.
The dosage is appropriately decided depending on the type of diseases, age, sex, body weight, degree of symptoms and the like of each patient to be treated, which is approximately within the range of from 1 to 1,000 mg per day per adult human in the case of oral administration and approximately within the range of from 0.01 to 100 mg per day per adult human in the case of parenteral administration, and the daily dose can be divided into one to several doses per day.
The present invention is further illustrated in more detail by way of the following Reference Examples, Examples and Test Examples. However, the present invention is not limited thereto.